Chronic Pain and the Opioid Conundrum

C h ro n i c Pa i n an d t h e Opioid Conundrum Lynn R. Webster,

MD

KEYWORDS  Chronic pain  Opioid analgesics  Government  Policy  Practice guidelines KEY POINTS  Prescribed opioids for chronic noncancer pain pose risks for the individual and society in the form of diversion, misuse, abuse, addiction, and death.  Evidence supporting long-term use of opioids for the treatment of chronic noncancer pain is sparse, but it does appear that some carefully selected patients may indeed benefit from this treatment.  State regulatory bodies and other policymaking entities have instituted a number of efforts to halt nonmedical use (ie, abuse) of opioids, with attendant implications for clinical practice as well as patient access to pain treatment.  A clear understanding is essential for prescribers of opioids of the rapidly evolving, regulatory and policymaking developments, as clinical practice must comply with federal and state law.

INTRODUCTION

The conundrum of opioid prescribing is usually understood to refer to the need to adequately control pain in patients who derive benefits from opioids, while, at the same time, working to prevent misuse, addiction, overdose deaths, and other associated risks and side effects.1 The conundrum should not be construed to somehow weigh the lives lost to addiction or overdose against those lost to suicide due to uncontrolled pain, as neither category of loss is acceptable. LESSONS LEARNED FROM HISTORY

The opioid conundrum has always reflected the tension inherent in public discussion of agents that provide relief of excruciating pain, some of which was formerly untreatable, and the fear that long-term harm may result to the user. As early as the seventeenth century, English doctor Thomas Sydenham called laudanum (a mixture containing opium) “the most valuable drug in the world”; however, his colleague John Jones

Scientific Affairs, PRA Health Sciences, 3838 South 700 East, Suite 202, Salt Lake City, UT 84106, USA E-mail address: [email protected] Anesthesiology Clin 34 (2016) 341–355 http://dx.doi.org/10.1016/j.anclin.2016.01.002 anesthesiology.theclinics.com 1932-2275/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.

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declared that long-term use would cause “intolerable anxiety, and depression and a miserable death.”2 In recent years, public discussions of opioid use in clinical practice for chronic pain are often fraught with emotion, strong views, and barriers born of context, depending on the position of the commentator, whether pain physician, pain patient, addiction expert, law enforcement official, regulator, lawmaker, pharmaceutical industry representative, or other stakeholder. One constant throughout history has been that many people with chronic pain are stigmatized, relegated to a frequently invisible class in society. With the advent of the work in the 1950s of John Bonica, MD, often referred to as “the father” of modern pain medicine, a philosophy arose to treat people with pain humanely and professionally, using multidisciplinary care to address the biopsychosocial components of the experience of pain.3 Unfortunately, in the decades since, Bonica’s vision has not achieved widespread adoption, as a pure bio-medical model became easier to apply clinically than individualized treatment and more readily supported by financial interests that include the optimization of insurance payer profits and minimization of costs, as well as pharmaceutical industry profits.4 A cultural shift to address uncontrolled chronic pain, beginning in the early 1990s, resulted in an increase in the quantity of opioids prescribed, driven at times by the mistaken belief that opioids administered clinically were without significant risk.2,5 This change in practice was motivated by compelling evidence that pain in a medical setting often went unrelieved, a circumstance that contributed to uncontrolled pain becoming identified as a public health problem.5,6 A movement to define failure to control pain as professional misconduct ensued,6 and in 2010 the International Association for the Study of Pain adopted a declaration stating that access to pain management is a fundamental human right.7 With the dawn of the twenty-first century, the rise in opioid use to control chronic pain began to coincide with increases in harm associated with prescription opioids, including nonmedical use (ie, abuse) of opioids.8 This contributed to a climate of fear among clinicians who treat pain, including the following2,9:  Fear of contributing to nonmedical use, addiction, diversion, and overdose deaths;  Fear of risk to the clinician’s continued ability to practice medicine;  Fear of contributing to uncontrolled pain because of reluctance to prescribe when indicated;  Fear of actual or perceived failure to meet the standard of care, which, in turn, could lead to regulatory sanctions, such as suspension or revocation of the physician’s license to practice medicine or suspension or revocation of the physician’s federal controlled substances registration;  Fear of actual or perceived recklessness in prescribing, which, in turn, could lead to criminal prosecution by federal or state authorities. Brief Background on Chronic Pain

Chronic pain is precisely that: chronic. It is pain that lasts beyond the period expected for healing, generally defined as more than 3 months.10 Pain may begin as a symptom; however, when it persists, changes in the structure and function of the central nervous system (CNS) occur, making pain itself a disease.10 The prevalence of chronic pain in America has not diminished and is expected to increase as the population ages, giving urgency to the call for more and better solutions.11 More than 100 million Americans struggle with some level of chronic pain.10 Contributing to treatment complexity, many people with chronic pain have multiple

Chronic Pain and the Opioid Conundrum

issues that include comorbid psychiatric conditions,12,13 social pressures, isolation, and lack of community support. In addition, uncontrolled moderate-to-severe postsurgical pain is common, increasing health care costs, delaying recovery, and raising the risk for progression to chronic pain.14 Brief Background on Opioid-Related Death, Misuse, Abuse, Addiction

The wider availability of pharmaceuticals that has accompanied more liberal prescribing patterns has coincided with higher rates of overdose deaths, misuse, emergency department (ED) visits, and admissions for substance-abuse treatment involving opioids and other controlled substances. Figs. 1 and 2 illustrate the rise in opioidrelated deaths in the United States from 1999 to 2013,15,16 and how the trend coincides with opioid sales.15–17 Further findings include the following:  In 2013, 6.5 million Americans age 12 or older, representing 2.5% of the population, were current nonmedical users of prescription drugs, including opioids, stimulants, and benzodiazepines.18  Of the 16,235 deaths involving opioids, 6973 involved benzodiazepines.19 Indeed, most deaths involved more than one substance, with opioids and benzodiazepines a commonly seen combination.  In 2011, ED visits involving prescription opioids reached 420,040, up 153% from 2004.20 Similarly, ED visits involving benzodiazepines rose 124% over the same period and numbered 501,207 in 2011.  Admissions for substance-abuse treatment involving opiates other than heroin (ie, principally prescription opioids) have grown, rising from 2% of admissions in 2002 to 10% by 2012.21  The number of methadone deaths is disproportionate to the number of prescriptions written, as reported by the Centers for Disease Control and Prevention:

Fig. 1. Number of US drug poisoning deaths involving opioid analgesics, 1999–2013 (National Vital Statistics System Mortality Data). Drug poisoning deaths are identified using the International Classification of Diseases, Tenth Revision underlying cause of death codes X40–X44, X60–X64, X85, and Y10–Y14. Drug poisoning deaths involving opioid analgesics are the subset of drug poisoning deaths with a multiple cause of death code of T40.2–T40.4. (Data from Refs.15,16)

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Fig. 2. Rates of prescription opioid sales and deaths, 1999–2013 (National Vital Statistics System; automation of reports and consolidated orders system of the Drug Enforcement Administration). (Data from Refs.15–17)

methadone accounts for approximately 2% of opioid prescriptions written but is associated with one-third of deaths.22 In 2009, 6 times as many people died of methadone-related overdose as a decade before.22 OPIOID EFFECTIVENESS DATA

A 2015 systematic review performed for a National Institutes of Health workshop to evaluate the evidence on opioids for chronic pain found the following23:  Insufficient evidence to determine the effectiveness of long-term opioid therapy for improving chronic pain and function;  A dose-dependent risk for serious harms, such as abuse, addiction, overdose, fractures, and cardiovascular events;  Inadequate data to identify the medical conditions in patients for whom opioid use is most appropriate;  Inadequate data to identify optimal regimens;  Inadequate data to identify the treatment alternatives for those who are unlikely to benefit from opioids. The following findings are from a review of more than 70 randomized trials that evaluated the benefits and harms of opioids for chronic noncancer pain24:  Nearly all were short-term efficacy studies, lasting 16 weeks or less;  Only 3 studies followed patients for longer than 4 months;  Most studies excluded patients at high risk for substance abuse or with significant medical or psychiatric comorbidities. The lack of long-term studies is frequently held up as evidence that no benefit has been demonstrated; however, this conclusion would overstate what the evidence allows. There are some studies (Table 1),25–40 as well as clinical experience, that suggest that some patients do well long-term. Despite limitations that include open-label design, differing methodologies and inclusion/exclusion criteria and lack of nonopioid comparison groups, the studies in Table 1 counter the argument that no evidence of

Chronic Pain and the Opioid Conundrum

Table 1 Studies beyond 90 days of opioid effectiveness for chronic pain Maximum Observation Duration, mo No. Evaluable

Study, Year

Study Type

Noble et al,25 2008

Systematic review, metaanalysis

24

3079

Portenoy et al,26 2007

Prospective registry

36

219

Caldwell et al,27 2002

Open-label extension

7.5

295

Roth et al,28 2000

Open-label extension

6 12 18

58 41 15

Rauck et al,29 2008

Open-label, nonrandomized 6

126

McIlwain & Andieh,30 2005

Open-label extension

12

153

Wild et al,31 2010

Open-label, randomized, phase 3

12

1117

Allan et al,32 2005

Open-label, randomized, parallel group,

13

680

Bettoni,33 2006

Prospective, nonrandomized 24

14

Collado & Torres,34 2008 Prospective, nonrandomized 6

215

Fredheim et al,35 2006

Open-label, prospective, nonrandomized

9

12

Milligan et al,36 2001

Open-label, prospective, nonrandomized

12

532

Mystakidou et al,37 2003 Open-label, prospective, nonrandomized

10

529

Breivik et al,38 2010

Randomized, double-blind, placebo-controlled

6

199

Wen et al,39 2010

Open-label, extension

3 6 12

1127 728 154

Richarz et al,40 2013

Open-label, extension

12

112

Data from Refs.25–40

long-term benefit exists. Furthermore, the ethical difficulty of administering placebo to people with severe pain for prolonged periods of time precludes long-term doubleblind, placebo-controlled studies. Some additional findings illuminate several points for discussion, as follows:  Many patients discontinue opioids because of inadequate analgesia or side effects25;  Opioids continue to demonstrate benefits for some patients who are able to continue treatment for at least 6 months25;  There is significant confounding of effectiveness by the high prevalence of psychiatric comorbidities in the population of opioid-treated patients41;  Noncompliance with opioid therapy increases with mental health issues.42 These findings must be factored into the discussion, while, at the same time, recognition is necessary that not all patients are likely to benefit with long-term opioid therapy and that the accompanying risks are significant.

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ABUSE-DETERRENT TECHNOLOGY

Abuse-deterrent technologies in opioid formulations developed by the pharmaceutical industry have begun to demonstrate effectiveness in deterring nonmedical use, although results show lack of complete protection.43–45 Studies of the reformulated oxycodone hydrochloride (HCl) extended-release (ER) tablets (Purdue Pharma LP, Stamford, CT), available since 2010, showed a decrease in preference by opioiddependent subjects for oxycodone HCl ER as a primary drug of abuse, as well as reductions in diversion and poison center exposures after introduction of the reformulated product.43–45 The largest drop was seen in nonoral routes of abuse, which decreased by 66%.43 These results may not translate to less overall opioid abuse in the population, particularly if non–abuse-deterrent formulations remain available and are preferred by third-party payers as affordable pain treatment options. THE PROBLEM WITH PAYER POLICIES

The health insurance system in the United States exacerbates the problem of suboptimal pain management. Lack of willingness by third-party payers to cover coordinated interdisciplinary care programs and certain nonmedication therapies (eg, physical therapy, psychotherapeutic modalities, complementary and alternative medicine approaches) as well as payer restrictions that limit the use of more expensive nonopioid analgesic medications often leave patients to suffer or drive them toward less effective treatments and drug therapies (both licit and illicit) with accompanying risk for a substance-use disorder.4 Interdisciplinary care delivered in the context of a biopsychosocial model has a strong evidence base for efficacy and cost-effectiveness.46 Unfortunately, access to interdisciplinary care is decreasing in the United States, even while access is increasing in other industrialized nations.46 The number of US interdisciplinary pain care programs dropped from more than 1000 in 1999 to approximately 150 as of 2011, with roughly one available interdisciplinary program for every 670,000 sufferers of chronic pain.46 An overhaul of the payer system would be necessary to require adequate coverage for evidencebased alternatives to opioids for chronic pain. OPIOID RESEARCH STILL NEEDED

Given the crisis of unmet need for pain control, the question grows in importance of why the dearth of research and investment into effective and safer analgesic therapies is allowed to continue. At minimum, the following research questions pursuant to opioids and pain deserve greater focus:  How does the individual patient’s genome contribute to pain processing and opioid responsiveness?  Why do different patients vary in response to different opioid molecules?  How may a risk-benefit ratio be determined before, not after, opioids are prescribed?  Is dose alone responsible for greater opioid-related harm, or do higher doses prescribed in patients with high pain intensity and more comorbidities lead to poorer outcomes?  Which alternatives to opioids are safe and effective (eg, abuse-deterrent opioid formulations, cannabinoids, psychological and behavioral therapies, complementary and integrative therapies, such as mindfulness)?  Were some opioid-related, overdose deaths that were attributed to unintentionality actually intentional to escape unrelenting physical pain or emotional misery from a multitude of psychological, social, and spiritual deficits?

Chronic Pain and the Opioid Conundrum

REGULATORY CONSIDERATIONS

Efforts directed toward minimizing misuse, abuse, addiction, overdose mortality, and other harms associated with opioid use have included initiatives directed at limiting opioid dose and treatment duration.47 However, severe chronic pain is not a shortterm problem. Policy proposals aimed at decreasing harm are not feasible or humane if they skirt this reality. Upper Dose Limits: Washington State

A guideline first published in 2007 by the Washington State Agency Medical Directors Group (AMDG) stated the following48:  Doses higher than 120-mg oral morphine equivalents per day should rarely be given and “only after pain management consultation.” Elements from the guideline were passed into state law and began to be enforced in 2012. In addition to the dose limit that triggered expert consultation, the bill required close monitoring of patient outcomes. Problems raised with this dose limit included the following47,49:  Pain specialists for consultation were in short supply;  The 120-mg ceiling guideline was reached without sufficient scientific support;  The guideline specified a diagnosis of “noncancer” pain, setting up possible discrimination;  Potential risk of false security in believing doses less than 120 mg are always “safe”;  Failure to emphasize the danger of cointoxication with benzodiazepines and other CNS depressants;  Insufficient attention to harm-contributing factors, such as nonmedical opioid use, drug formulation impact, patient mental health and nonadherence, prescriber error, suicide, polysubstance use, and variable individual pharmacokinetics;  Failure to address the increased risk of harm unique to the use of methadone to treat noncancer pain;  Potential to worsen patient access to care, especially if the guideline were to become interpreted to be a “standard of care” and embraced more broadly (eg, other states, nationally). An update to the AMDG guideline, issued in 2015, retained the 120-mg “yellow flag,” citing evidence to support it, but also put new emphasis on the need for caution at any dose.50 Risk Evaluation and Mitigation Strategy Programs

The Food and Drug Administration (FDA) approved a risk evaluation and mitigation strategy (REMS) for ER and long-acting (LA) opioids to ensure benefits outweigh risks.51 Manufacturers of opioids are now required to distribute medication guides and to provide prescribers with education programs, created through accredited continuing education providers and based on an FDA Blueprint. Prescribing clinicians are strongly encouraged to complete a REMS education program. Although the FDA action did not cover immediate-release formulations, prescribing clinicians should take equal care to assess risk and provide optimal follow-up and monitoring for patients on any controlled substances prescribed during the course of pain management.

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Food and Drug Administration Labeling Changes

In response to requests to make labeling changes for opioid analgesics, the FDA enacted the following labeling changes for ER/LA opioids52:    

Emphasized the need to individualize treatment; Stated the pain must be severe enough to indicate treatment with ER/LA opioids; Recommended use only when alternatives are determined to be inadequate; Urged caution regarding coadministration with alcohol and with centrally-acting sedating medications;  Placed firmer focus on assessment of patient daily activities and quality of life rather than pain scale alone;  Urged caution regarding opioid use during pregnancy, including the risk of newborn infants experiencing neonatal abstinence syndrome when the mother consumed chronic opioids during pregnancy;  Required studies beyond 12 weeks to assess risks of misuse, abuse, hyperalgesia, and addiction. Rescheduling of Hydrocodone

On October 6, 2014, the Drug Enforcement Administration (DEA) moved hydrocodone from Schedule III to the more strictly regulated Schedule II, triggering the following changes53:  Prescriptions became limited to no more than a 30-day supply;  Patients must see doctors for each new refill;  Prescriptions can no longer be phoned or faxed in. The DEA cited growing problems with opioid-related abuse, addiction, and overdose deaths as the reason for stricter regulatory action. In response to early indications that the regulation may be affecting patient access to pain medications, an Internet survey was conducted to gather information on the first 100 days of hydrocodone rescheduling. Administered through the National Fibromyalgia & Chronic Pain Association, the survey found that two-thirds of participants reported trouble filling prescriptions for hydrocodone combination products, and 15% reported negative impacts on physician-patient relationships.54 The survey had 3000 participants, many with multiple pain diagnoses that included fibromyalgia (91%), low back pain (62%), and neck pain (44%). PRINCIPLES OF PRACTICE

Opioids are imperfect but may be necessary even longterm for some patients. Patients being considered for chronic opioid therapy must be carefully evaluated, stratified by risk for problematic opioid usage, and monitored for therapeutic effects, adverse events, aberrant drug-related behaviors, and progress toward treatment goals. Practice guidelines are available, and all state, federal, and local controlled substances law must be followed. Regardless, pain is still a subjective experience and one that requires considerable clinical experience, judgment, and resources to treat effectively. Opioid Guidelines from Professional Medical Societies

Several opioid-prescribing guidelines are available to assist clinicians. A published systematic review of 13 such guidelines gave high ratings to 2 publications55: the joint guideline of the American Pain Society (APS) and American Academy of Pain Medicine (AAPM)56 and the guideline from the Canadian National Opioid Use Guideline

Chronic Pain and the Opioid Conundrum

Table 2 Screening tools to assess patient risk before prescribing opioids Tool

No. of Items

Method of Administration

Opioid Risk Tool

5

Patient

Screener and Opioid Assessment for Patients with Pain

24, 14, or 5

Patient

Diagnosis, Intractability, Risk, and Efficacy Score

7

Clinician

Data from Refs.56,59–62

Group.57,58 An expert panel took more than a year and reviewed 8000 studies to produce the joint APS/AAPM guideline.56 Seven other guidelines were found to be of intermediate quality, and 4 guidelines were not recommended for use. Guidelines found common ground in several areas, including recommending that prescribers of opioids do the following55–58:  Obtain a detailed history and physical examination;  Assess for abuse and addiction, perhaps using an opioid-specific tool56,59–62(Table 2);  Initiate an individual trial and titration regimen;  Periodically reassess the patient for function, progress toward treatment goals, adverse events, and adherence to medical direction; see Table 3 for suggested clinical monitoring tools63,64;  Possess special knowledge to prescribe methadone;  Recognize risks of fentanyl patches;  Titrate cautiously;  Reduce doses by 25% to 50% when rotating to a different opioid;  Use opioid risk assessment tools;  Use written treatment agreements;  Use urine drug testing to check for patient adherence;  Check the state prescription drug monitoring database where available;  Treat high-risk patients with more frequent and stringent monitoring and comanagement with mental health and addiction specialists;  Consider reasons for repeated escalations in opioid dose;  Consider opioid rotation with adverse effects or ineffective analgesia;  Discontinue opioid therapy through tapering when repeated aberrant drugrelated behaviors are observed. These principles of practice coincide with state practice requirements, which are frequently listed on the Web site of each state’s medical board or professional licensing agency. Many states have adopted standards set by the Federation of State Medical Boards (FSMB), which has issued and updated a Model Policy65 (Box 1). Table 3 Monitoring tools after initiation of opioid therapy Tool

No. of Items

Pain Assessment and Documentation Tool

41

Clinician

Current Opioid Misuse Measure

17

Patient

Data from Refs.63,64

Method of Administration

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Box 1 FSMB model policy for the use of opioid analgesics in the treatment of chronic pain 1. Thorough evaluation and risk stratification with an indication for prescribed opioids supported by history, physical, and appropriate tests before prescribing 2. Written treatment plan with stated objectives and consideration of pharmacologic and nonpharmacologic treatment modalities as appropriate 3. Informed consent on risks/benefits and an agreement for treatment outlining physician/ patient responsibilities 4. Opioid trial following consideration of safer alternatives at lowest possible dose, titrated to effect 5. Regular review of the course of treatment to evaluate progress toward treatment objectives and to monitor adherence with medical direction, adjusting treatment when necessary, using “5 A’s”: analgesia, activity, adverse effects, aberrant substance-related behaviors, and affect 6. Periodic drug testing to ensure patient adherence (eg, urine testing, pill counts, prescription database checks) 7. Referrals for additional and specialist evaluation and treatment if necessary 8. Continually weigh benefits versus risk of opioid therapy and institute opioid discontinuation plan if necessary (eg, resolution of pain, intolerable side effects, inadequate analgesia, significant aberrant use, deteriorating function) 9. Accurate and complete records that include documentation of all of the above and all prescription orders 10. Familiarity and compliance with all state and federal laws and regulations regarding controlled substances Abbreviation: FSMB, Federation of State Medical Boards. Data from Ref.65

Health Care Providers Are Not Alone

Co-occurrence of mental health disorders with chronic pain places patients at higher risk for misuse, drug-drug interactions, and overdose. Consultation should be considered when health care providers feel that the patient may benefit from other resources.56 Keep in mind there is an approximately 50% overlap of pain disorders with psychiatric disorders.66–69 Furthermore, there is an approximately 60% overlap of psychiatric disorders with addiction disorders.70 For long-term pain management, opioids are only one tool; interdisciplinary and multimodal care are optimal.71 Patients may not benefit from opioids as follows:71  Opioids appear to be causing significant side effects;  Opioids do not seem to be effectively leading to attainment of specified goals;  Patients gain analgesia from opioid therapy but are at risk of misuse or overuse. SUMMARY

 Opioids are an imperfect option for all pain states but the only treatment that works for many pain conditions;  Whenever possible, an equally efficacious nonopioid therapy should be offered, even if the cost is greater;  When initiating opioid therapy, risk assessment leading to risk stratification should be implemented;

Chronic Pain and the Opioid Conundrum

 To support optimal clinical decisions regarding treatment choices, significant change is necessary to the payer system;  Familiarity with opioid practice guidelines, regulatory requirements, and laws pertaining to controlled substances is an obligation of all prescribers. ACKNOWLEDGMENTS

Beth Dove of Dove Medical Communications, LLC, Salt Lake City, Utah, provided medical writing for this article. REFERENCES

1. Ballantyne JC. Opioid analgesia: perspectives on right use and utility. Pain Physician 2007;10:479–91. 2. Rhodin A. The rise of opiophobia: is history a barrier to prescribing? J Pain Palliat Care Pharmacother 2006;20:31–2. 3. Bonica JJ. The management of pain, with special emphasis on the use of block in diagnosis, prognosis and therapy. Philadelphia: Lea & Febiger; 1953. 4. Schatman ME, Webster LR. The health insurance industry: perpetuating the opioid crisis through policies of cost-containment and profitability. J Pain Res 2015;8:153–8. 5. Bennett DS, Carr DB. Opiophobia as a barrier to the treatment of pain. J Pain Palliat Care Pharmacother 2002;16:105–9. 6. Brennan F, Carr DB, Cousins MJ. Pain management: a fundamental human right. Anesth Analg 2007;105:205–21. 7. International Pain Summit of the International Association for the Study of Pain. Declaration of Montre´al: declaration that access to pain management is a fundamental human right. J Pain Palliat Care Pharmacother 2011;25:29–31. 8. Gilson AM, Ryan KM, Joranson DE, et al. A reassessment of trends in the medical use and abuse of opioid analgesics and implications for diversion control: 1997-2002. J Pain Symptom Manage 2004;28:176–88. 9. Webster LR, Dove B. Avoiding opioid abuse while managing pain: a guide for practitioners. North Branch (MN): Sunrise River Press; 2007. 10. Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: National Academies Press (US); 2011. 11. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646–56. 12. Tsang A, Von Korff M, Lee S, et al. Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J Pain 2008;9:883–91. 13. Ohayon MM, Schatzberg AF. Chronic pain and major depressive disorder in the general population. J Psychiatr Res 2010;44:454–61. 14. McGrath B, Elgendy H, Chung F, et al. Thirty percent of patients have moderate to severe pain 24 hr after ambulatory surgery: a survey of 5,703 patients. Can J Anaesth 2004;51:886–91. 15. Chen LH, Hedegaard H, Warner M. QuickStats: rates of deaths from drug poisoning and drug poisoning involving opioid analgesics—United States, 1999–2013. MMWR Morb Mortal Wkly Rep 2015;64:32.

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